Intracorneal lens implantation with a cross-linked cornea

ABSTRACT

A method of intracorneal lens implantation with a cross-linked cornea is disclosed herein. The method includes forming a pocket in a cornea of an eye, applying a photosensitizer inside the pocket so that the photosensitizer permeates at least a portion of the tissue bounding the pocket, the photosensitizer facilitating cross-linking of the tissue bounding the pocket; irradiating the cornea so as to activate cross-linkers in the portion of the tissue bounding the pocket, and thereby kill cells therein; inserting a lens implant into the pocket; and applying laser energy to the lens implant in the pocket using a laser so as to correct refractive errors of the lens implant and/or the eye in a non-invasive manner. In other embodiments, a lens implant is soaked in a cross-linking solution that includes a photosensitizer prior to being inserted into the pocket in the cornea of an eye.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application claims priority to U.S. Provisional PatentApplication No. 62/290,089, entitled “Method of Altering the RefractiveProperties of the Eye”, filed on Feb. 2, 2016, and is acontinuation-in-part of application Ser. No. 15/230,445, entitled“Corneal Lenslet Implantation With A Cross-Linked Cornea”, filed Aug. 7,2016, which claims priority to U.S. Provisional Patent Application No.62/360,281, entitled “Method of Altering the Refractive Properties of anEye”, filed on Jul. 8, 2016, and is a continuation-in-part ofapplication Ser. No. 14/709,801, entitled “Corneal Transplantation WithA Cross-Linked Cornea”, filed May 12, 2015, now U.S. Pat. No. 9,427,355,which claims priority to U.S. Provisional Patent Application No.61/991,785, entitled “Corneal Transplantation With A Cross-LinkedCornea”, filed on May 12, 2014, and to U.S. Provisional PatentApplication No. 62/065,714, entitled “Corneal Transplantation With ACross-Linked Cornea”, filed on Oct. 19, 2014, the disclosure of each ofwhich is hereby incorporated by reference as if set forth in theirentirety herein.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not Applicable.

NAMES OF THE PARTIES TO A JOINT RESEARCH AGREEMENT

Not Applicable.

INCORPORATION BY REFERENCE OF MATERIAL SUBMITTED ON A COMPACT DISK

Not Applicable.

BACKGROUND OF THE INVENTION 1. Field of the Invention

The invention generally relates to corneal transplantation and theimplantation of lens implants in the corneas of eyes. More particularly,the invention relates to methods for corneal lenslet implantation with across-linked cornea.

2. Background

Corneal scarring is a major cause of blindness, especially in developingcountries. There are various causes for corneal scarring, which include:bacterial infections, viral infections, fungal infections, parasiticinfections, genetic corneal problems, Fuch's dystrophy, and othercorneal dystrophies. A corneal transplant is often required if thecorneal scarring is extensive, and cannot be corrected by other means.However, there can be major complications associated with a cornealtransplant, such as corneal graft rejection wherein the transplantedcornea is rejected by the patient's immune system.

A normal emmetropic eye includes a cornea, a lens and a retina. Thecornea and lens of a normal eye cooperatively focus light entering theeye from a far point, i.e., infinity, onto the retina. However, an eyecan have a disorder known as ametropia, which is the inability of thelens and cornea to focus the far point correctly on the retina. Typicaltypes of ametropia are myopia, hypermetropia or hyperopia, andastigmatism.

A myopic eye has either an axial length that is longer than that of anormal emmetropic eye, or a cornea or lens having a refractive powerstronger than that of the cornea and lens of an emmetropic eye. Thisstronger refractive power causes the far point to be projected in frontof the retina.

Conversely, a hypermetropic or hyperopic eye has an axial length shorterthan that of a normal emmetropic eye, or a lens or cornea having arefractive power less than that of a lens and cornea of an emmetropiceye. This lesser refractive power causes the far point to be focusedbehind the retina.

An eye suffering from astigmatism has a defect in the lens or shape ofthe cornea converting an image of the point of light to a line.Therefore, an astigmatic eye is incapable of sharply focusing images onthe retina.

While laser surgical techniques, such as laser-assisted in situkeratomileusis (LASIK) and photorefractive keratectomy (PRK) are knownfor correcting refractive errors of the eye, these laser surgicaltechniques have complications, such as post-operative pain and dry eye.Also, these laser surgical techniques cannot be safely used on patientswith corneas having certain biomechanical properties. For example,corneal ectasia may occur if these laser surgical techniques are appliedto patients having thin corneas (e.g., corneas with thicknesses that areless than 500 microns).

Therefore, what is needed is a method for corneal transplantation thatreduces the likelihood that the implanted cornea will be rejected by thepatient. Moreover, a method is needed for corneal transplantation thatis capable of preserving the clarity of the transplanted cornea.Furthermore, there is a need for a method of corneal transplantationthat reduces the likelihood that the transplanted cornea will be invadedby migrating cells. Also, what is needed is a method for corneal lensletimplantation for modifying the cornea to better correct ametropicconditions. In addition, a method is needed for corneal lensletimplantation that prevents a lens implant from moving around inside thecornea once implanted so that the lens implant remains centered aboutthe visual axis of the eye. Further, what is needed is a method forintracorneal lens implantation for modifying the cornea to bettercorrect ametropic conditions.

BRIEF SUMMARY OF EMBODIMENTS OF THE INVENTION

Accordingly, the present invention is directed to one or more methods ofcorneal lenslet implantation with cross-linked corneas thatsubstantially obviate one or more problems resulting from thelimitations and deficiencies of the related art.

In accordance with one or more embodiments of the present invention,there is provided a method of intracorneal lens implantation with across-linked cornea. The method comprising the steps of: (i) forming apocket in a cornea of an eye so as to gain access to tissue bounding thepocket; (ii) after the pocket in the cornea has been formed, applying aphotosensitizer inside the pocket so that the photosensitizer permeatesat least a portion of the tissue bounding the pocket, thephotosensitizer facilitating cross-linking of the tissue bounding thepocket; (iii) irradiating the cornea so as to activate cross-linkers inthe portion of the tissue bounding the pocket, and thereby stiffen thecornea, prevent corneal ectasia of the cornea, and kill cells in theportion of the tissue bounding the pocket; (iv) after the portion of thetissue bounding the pocket has been stiffened and is devoid of cellularelements by the activation of the cross-linkers, inserting a lensimplant into the pocket; and (v) applying laser energy to the lensimplant in the pocket using a laser so as to correct refractive errorsof the lens implant and/or the eye in a non-invasive manner. In theseone or more embodiments, the step of irradiating the cornea so as toactivate cross-linkers in the portion of the tissue bounding the pocketonly kills the cells in the portion of the tissue bounding the pocket soas to leave only a thin layer of cross-linked collagen to preventrejection of the lens implant and/or encapsulation by fibrocytes, whilepreventing post-operative dry eye formation.

In a further embodiment of the present invention, the step of applyinglaser energy to the lens implant in the pocket further comprisesapplying laser energy to the lens implant in the pocket using atwo-photon or multi-photon laser so as to modify the index of refractionof a discrete internal part of the lens implant in a non-invasivemanner, while preventing post-operative dry eye formation.

In yet a further embodiment, the laser energy applied by the two-photonor multi-photon laser has a predetermined energy level below an opticalbreakdown power level of the two-photon or multi-photon laser.

In still a further embodiment, prior to the step of applying laserenergy to the lens implant in the pocket, performing the additionalsteps of: (vi) generating, by using a specially programmed dataprocessing device, a virtual model of the lens implant so that a newindex of refraction of the lens implant at the focal point of thetwo-photon or multi-photon laser is capable of being determined prior tothe application of the two-photon or multi-photon laser; and (vii)focusing, by using the specially programmed data processing device, thetwo-photon or multi-photon laser non-invasively outside the eye inaccordance with the virtual model generated for the lens implant.

In yet a further embodiment, a photorefractive keratectomy (PRK)procedure is not performed on the front surface of the cornea so thatthe front surface of the cornea is not required to be ablated by anexcimer laser.

In still a further embodiment, a laser-assisted in situ keratomileusis(LASIK) procedure is not performed on the cornea so that a flap is notrequired to be formed in the cornea, thereby preventing a formation ofdry eye in a patient resulting from the severing of the corneal nervessupplying the front surface of the cornea.

In yet a further embodiment, the portion of the tissue bounding thepocket comprises stromal tissue of the cornea.

In still a further embodiment, the step of applying the photosensitizerinside the pocket comprises injecting the photosensitizer inside thepocket using a needle.

In yet a further embodiment, the method further comprises the steps of:(vi) after the lens implant has been inserted into the pocket, injectingan additional amount of photosensitizer into the pocket; and (vii)irradiating the cornea an additional time so as to further stiffenstromal tissue of the cornea and expand the area of acellularcollagenous stromal tissue surrounding the lens implant to preventrejection of the lens implant and/or encapsulation of the lens implantby fibrocytes, while preventing post-operative dry eye formation.

In still a further embodiment, the photosensitizer comprises riboflavin.

In yet a further embodiment, the step of irradiating the cornea so as toactivate cross-linkers in the portion of the tissue bounding the pocketcomprises irradiating the cornea with ultraviolet light.

In still a further embodiment, the step of forming the pocket in thecornea of the eye includes cutting the pocket using a femtosecond laseror a mechanical keratome.

In yet a further embodiment, the step of applying laser energy to thelens implant in the pocket further comprises applying laser energy tothe lens implant using one of a femtosecond laser, a two-photon laser,or a multi-photon laser so as to increase the index of refraction of aparticular area of the lens implant, and thereby convert the lensimplant from a monofocal lens to a bifocal lens or a trifocal lens.

In still a further embodiment, the particular area of the lens implantthat the index of refraction is increased comprises one of: (i) an areaslightly below the cornea or the central visual axis of the eye, (ii) acentral area centrally located on the central visual axis of the eye,and (iii) a peripheral area circumscribing the central visual axis ofthe eye.

In accordance with one or more other embodiments of the presentinvention, there is provided a method of intracorneal lens implantationwith a cross-linked cornea. The method comprising the steps of: (i)soaking a lens implant in a cross-linking solution that includes aphotosensitizer, the lens implant having a predetermined shape forchanging the refractive properties of an eye; (ii) forming a pocket in acornea of the eye; (iii) after the pocket in the cornea has been formed,inserting the lens implant with the photosensitizer thereon inside thepocket so that the photosensitizer permeates at least a portion of thetissue bounding the pocket, the photosensitizer facilitatingcross-linking of the portion of the tissue bounding the pocket; (iv)irradiating the cornea so as to activate cross-linkers in the portion ofthe tissue bounding the pocket, and thereby stiffen the cornea, preventcorneal ectasia of the cornea, and kill cells in the portion of thetissue bounding the pocket; and (v) applying laser energy to the lensimplant in the pocket using a laser so as to correct the remainingrefractive errors of the eye in a non-invasive manner. In these one ormore embodiments, the step of irradiating the cornea so as to activatecross-linkers in the portion of the tissue bounding the pocket onlykills the cells in the portion of the tissue bounding the pocket so asto leave only a thin layer of cross-linked collagen to prevent rejectionof the lens implant and/or encapsulation by fibrocytes, while preventingpost-operative dry eye formation.

In a further embodiment of the present invention, the photosensitizer ofthe cross-linking solution comprises riboflavin.

In yet a further embodiment, the step of irradiating the cornea so as toactivate cross-linkers in the portion of the tissue bounding the pocketcomprises irradiating the cornea with ultraviolet light.

In still a further embodiment, the step of inserting the lens implantwith the photosensitizer thereon inside the pocket comprises insertingthe lens implant using forceps.

In yet a further embodiment, the lens implant that is inserted insidethe pocket in the cornea is flexible and porous.

In still a further embodiment, the lens implant comprises a hybrid lensimplant with an organic outer portion and a synthetic inner portion, theorganic outer portion of the hybrid lens implant being made from atransparent, hydrophilic organic polymer, and the synthetic innerportion of the hybrid lens implant being made from a transparent, gaspermeable, porous flexible polymer.

In yet a further embodiment, the lens implant has one of: (i) a concavesurface to correct myopic refractive errors, (ii) a convex surface tocorrect hyperopic refractive errors, or (iii) a toric shape to correctastigmatic refractive errors.

In still a further embodiment, the step of applying laser energy to thelens implant in the pocket further comprises applying laser energy tothe lens implant in the pocket using a two-photon or multi-photon laserso as to modify the index of refraction of a discrete internal part ofthe lens implant to correct the remaining refractive errors of the eyein a non-invasive manner, while preventing post-operative dry eyeformation.

In yet a further embodiment, prior to the step of applying laser energyto the lens implant in the pocket, performing the additional steps of:(vi) generating, by using a specially programmed data processing device,a virtual model of the lens implant so that a new index of refraction ofthe lens implant at the focal point of the two-photon or multi-photonlaser is capable of being determined prior to the application of thetwo-photon or multi-photon laser; and (vii) focusing, by using thespecially programmed data processing device, the two-photon ormulti-photon laser non-invasively outside the eye in accordance with thevirtual model generated for the lens implant.

In accordance with yet one or more other embodiments of the presentinvention, there is provided a method of intracorneal lens implantationwith a cross-linked cornea. The method comprising the steps of: (i)soaking a lens implant in a cross-linking solution that includes aphotosensitizer, the lens implant having a predetermined shape forchanging the refractive properties of an eye; (ii) forming a pocket in acornea of the eye; (iii) after the pocket in the cornea has been formed,inserting the lens implant with the photosensitizer thereon inside thepocket so that the photosensitizer permeates at least a portion of thetissue bounding the pocket, the photosensitizer facilitatingcross-linking of the portion of the tissue bounding the pocket; (iv)applying laser energy to the lens implant in the pocket using a laser soas to correct the remaining refractive errors of the eye in anon-invasive manner; and (v) after the laser energy has been applied tothe lens implant, irradiating the cornea so as to activate cross-linkersin the portion of the tissue bounding the pocket, and thereby stiffenthe cornea, prevent corneal ectasia of the cornea, and kill cells in theportion of the tissue bounding the pocket. In these one or moreembodiments, the step of irradiating the cornea so as to activatecross-linkers in the portion of the tissue bounding the pocket onlykills the cells in the portion of the tissue bounding the pocket so asto leave only a thin layer of cross-linked collagen to prevent rejectionof the lens implant and/or encapsulation by fibrocytes, while preventingpost-operative dry eye formation.

It is to be understood that the foregoing general description and thefollowing detailed description of the present invention are merelyexemplary and explanatory in nature. As such, the foregoing generaldescription and the following detailed description of the inventionshould not be construed to limit the scope of the appended claims in anysense.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

The invention will now be described, by way of example, with referenceto the accompanying drawings, in which:

FIG. 1A is a partial side cross-sectional view of an eye having ascarred cornea, wherein substantially the entire thickness of the corneais scarred;

FIG. 1B is a partial side cross-sectional view of a donor corneaundergoing cross-linking;

FIG. 1C is a partial side cross-sectional view of the eye of FIG. 1A,wherein the scarred cornea is shown being removed;

FIG. 1D is a partial side cross-sectional view of the eye of FIG. 1A,wherein the cross-linked donor cornea is shown being implanted in thelocation previously occupied by the scarred cornea;

FIG. 2A is a partial side cross-sectional view of an eye having internalcorneal scar tissue;

FIG. 2B is a partial side cross-sectional view of the eye of FIG. 2A,wherein the scarred corneal tissue has been externally removed from theeye;

FIG. 2C is a partial side cross-sectional view of the eye of FIG. 2A,wherein a cross-linked donor cornea is shown being implanted in thelocation previously occupied by the scarred corneal tissue;

FIG. 3A is a partial side cross-sectional view of an eye having internalcorneal scar tissue;

FIG. 3B is a partial side cross-sectional view of the eye of FIG. 3A,wherein the scarred corneal tissue is shown being internally removedfrom the eye;

FIG. 3C is a partial side cross-sectional view of the eye of FIG. 3A,wherein a cross-linked donor cornea is shown being implanted in thelocation previously occupied by the scarred corneal tissue;

FIG. 4A is a partial side cross-sectional view of an eye having aT-shaped corneal scar and/or diseased tissue portion;

FIG. 4B is another partial side cross-sectional view of a donor corneaundergoing cross-linking;

FIG. 4C is a partial side cross-sectional view illustrating a T-shapedportion of the cross-linked donor cornea being cut out from a remainderof the donor cornea;

FIG. 4D is a partial side cross-sectional view of the eye of FIG. 4A,wherein the T-shaped scarred and/or diseased portion of corneal tissuehas been removed from the eye;

FIG. 4E is a partial side cross-sectional view of the eye of FIG. 4A,wherein the cross-linked T-shaped donor cornea portion is shown beingimplanted in the location previously occupied by the scarred and/ordiseased corneal tissue portion;

FIG. 5A illustrates an alternative configuration for the cross-linkeddonor cornea implant, wherein the donor cornea implant has a dumbbellshape;

FIG. 5B illustrates another alternative configuration for thecross-linked donor cornea implant, wherein the donor cornea implant hasa reversed or upside down T-shape;

FIG. 6A is a side cross-sectional view of a host eye prior to antransplant procedure;

FIG. 6B is another side cross-sectional view of the host eye of FIG. 6A,which illustrates a creation of a corneal pocket therein;

FIG. 6C is another side cross-sectional view of the host eye of FIG. 6A,which illustrates an implantation of the cross-linked lamellar lensletinto the host eye;

FIG. 7A is a partial side cross-sectional view of a donor cornea beingcross-linked prior to being shaped for use in a transplant procedure;

FIG. 7B is another partial side cross-sectional view of the donor corneaof FIG. 7A, which illustrates the cutting of a cross-linked lamellarlenslet from a remainder of the cross-lined donor cornea;

FIG. 7C is a side cross-sectional view of the cross-linked lamellarlenslet after it has been appropriately shaped and removed from thedonor cornea of FIGS. 7A and 7B;

FIG. 8 is a partial side cross-sectional view illustrating the formationof a two-dimensional cut into a cornea of an eye, according to anotherembodiment of the invention;

FIG. 9 is another partial side cross-sectional view of the eye of FIG.8, which illustrates the creation of a three-dimensional pocket in thecornea of the eye;

FIG. 10 is yet another partial side cross-sectional view of the eye ofFIG. 8, which illustrates the injection of a photosensitizer into thethree-dimensional pocket in the cornea of the eye;

FIG. 11A is still another partial side cross-sectional view of the eyeof FIG. 8, which illustrates the irradiation of the stromal tissuesurrounding the three-dimensional pocket of the eye using ultravioletradiation delivered from outside of the cornea;

FIG. 11B is yet another partial side cross-sectional view of the eye ofFIG. 8, which illustrates the irradiation of the stromal tissuesurrounding the three-dimensional pocket of the eye using a fiber opticdelivering ultraviolet radiation inside the three-dimensional pocket,according to an alternative embodiment of the invention;

FIG. 12 is still another partial side cross-sectional view of the eye ofFIG. 8, which illustrates a lens implant inserted into the pocket so asto change the refractive properties of the eye;

FIG. 13 is yet another partial side cross-sectional view of the eye ofFIG. 8, which illustrates the reinjection of a photosensitizer into thethree-dimensional pocket with the lens implant disposed therein so thatthe cross-linking procedure may be repeated;

FIG. 14 is still another partial side cross-sectional view of the eye ofFIG. 8, which illustrates the re-irradiation of the stromal tissuesurrounding the three-dimensional pocket of the eye during therepetition of the cross-linking procedure;

FIG. 15 is a side cross-sectional view illustrating the creation of alens implant from an organic block of polymer using a excimer laser;

FIG. 16 is a side cross-sectional view illustrating the cutting of alens implant from an organic block of polymer using a femtosecond laser;

FIG. 17 is a side cross-sectional view illustrating a lens implant thathas been formed using a three-dimensional printing technique or amolding technique;

FIG. 18 is a front view of a cornea of an eye, according to yet anotherembodiment of the invention;

FIG. 19 is another front view of the cornea of the eye of FIG. 18,wherein a square-shaped intrastromal pocket has been formed in thecornea of the eye;

FIG. 20 is yet another front view of the cornea of the eye of FIG. 18,wherein a circular three-dimensional portion of tissue having a firstdiameter has been removed from the area within the square-shapedintrastromal pocket;

FIG. 21 is still another front view of the cornea of the eye of FIG. 18,wherein a circular three-dimensional portion of tissue having seconddiameter has been removed from the area within the square-shapedintrastromal pocket, the second diameter of the circularthree-dimensional portion of tissue in FIG. 21 being larger than thefirst diameter of the circular three-dimensional portion of tissue inFIG. 20;

FIG. 22 is yet another front view of the cornea of the eye of FIG. 18,wherein a circular lens implant has been implanted in the area where thecircular three-dimensional portion of tissue has been removed, andwherein a photosensitizer is being injected into the pocket in thecornea of the eye;

FIG. 23 is still another front view of the cornea of the eye of FIG. 18,wherein the circular lens implant is shown in the area where thecircular three-dimensional portion of tissue was removed;

FIG. 24A is a partial side cross-sectional view illustrating the formingof a pocket in an eye, according to an embodiment of the invention;

FIG. 24B is a front view of the eye of FIG. 24A, which illustrates theforming of the pocket in the eye;

FIG. 25A is another partial side cross-sectional view of the eye of FIG.24A, which illustrates the irradiation of the stromal tissue surroundingthe pocket of the eye;

FIG. 26A is yet another partial side cross-sectional view of the eye ofFIG. 24A, which illustrates the insertion of a lens implant into thepocket so as to change the refractive properties of the eye;

FIG. 26B is a front view of the eye of FIG. 24A, which illustrates theinsertion of the lens implant into the pocket of the eye;

FIG. 27A is still another partial side cross-sectional view of the eyeof FIG. 24A, which illustrates the application of laser energy to thelens implant in the pocket so as to correct refractive errors of thelens implant and/or the eye in a non-invasive manner; and

FIG. 27B is a front view of the eye of FIG. 24A, which illustrates thelens implant in the eye after the refractive power of the lens implanthas been modified by the application of the laser energy.

Throughout the figures, the same elements are always denoted using thesame reference characters so that, as a general rule, they will only bedescribed once.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

A first illustrative embodiment of a corneal transplant procedure with across-linked cornea is shown in FIGS. 1A-1D. The corneal transplantprocedure illustrated in FIGS. 1A-1D involves full corneal replacementof the scarred or diseased cornea by the donor cornea. In other words,FIGS. 1A-1D illustrate a penetrating keratoplasty procedure wherein thefull thickness of the scarred or diseased cornea is replaced with across-linked donor cornea (i.e., a full-thickness corneal transplant).

Referring initially to FIG. 1A, it can be seen that substantially theentire thickness of the cornea 16 of the eye 10 is scarred and/ordiseased (i.e., scarred, diseased, or scarred and diseased). FIG. 1Aalso illustrates the lens 12 and iris 14 of the eye 10, which arelocated posteriorly of the cornea 16. In this embodiment, it isnecessary to replace substantially the entire thickness of the cornea 16with a donor cornea.

In FIG. 1B, the cross-linking 18 of the clear donor cornea 20 isdiagrammatically illustrated. As depicted in FIG. 1B, only the frontportion 20 a of the donor cornea 20 is cross-linked. That is, thecross-linking does not extend all the way to the rear portion 20 b ofthe donor cornea 20. It is to be understood that the cross-linking 18 ofthe donor cornea 20 may also be done after implanting the donor corneainto the eye of the patient, rather than before implantation as shown inthe illustrative example of FIGS. 1A-1D. Also, it is to be understoodthat all or just a part of the donor cornea 20 may be cross-linked.

In the illustrative embodiments described herein (i.e., as depicted inFIGS. 1A-1D, 2A-2C, and 3A-3C), the cross-linking of the clear donorcornea may comprise the steps of: (i) applying a photosensitizer to thedonor cornea, the photosensitizer facilitating cross-linking of thedonor cornea; and (ii) irradiating the donor cornea with ultravioletlight so as to activate cross-linkers in the donor cornea and therebystrengthen the donor cornea. The photosensitizer may comprise riboflavinor a solution comprising a liquid suspension having nanoparticles ofriboflavin. The cross-linker may have between about 0.1% Riboflavin toabout 100% Riboflavin or any other suitable range or specific percentagetherein. The ultraviolet radiation or rays used to irradiate the donorcornea may be between about 370 nanometers and about 380 nanometers (orbetween 370 nanometers and 380 nanometers). The radiation is preferablyabout 3 mW or more as needed and emanates from a laser source at about a3 cm distance from the donor cornea for about 30 minutes or less. Thetime of the exposure can vary depending on the light intensity, focus,and the concentration of riboflavin. However, the ultraviolet radiationcan be applied at any suitable distance, time or wavelength. Preferably,cross-linking the donor cornea does not significantly change therefractive power of the donor cornea; however, if desired, cross-linkingcan change the refractive power of the donor cornea to any suitabledegree.

In addition to Riboflavin, other suitable cross linking agents are lowcarbon carbohydrates, such as pentose sugar (e.g., ribose) or hexosesugar (e.g., glucose), or complex carbohydrates. Other crosslinkingagents may include Transaminidases, transglutaminases or anaturally-derived cross-linker named malic acid derivative (MAD)concentrations higher than 30 mM, commercially available cross-linkerssuch as 1-ethyl-3-(3(′-dimethylaminopropyl) carbodiimide (EDC), orethyl-3(3-dimethylamino) propyl carbodiimide (EDC), etc. Thecross-linking may also be done postoperatively by the application ofother crosslinking agents, such as Triglycidylamine (TGA) synthesizedvia reacting epichlorhydrin and a carbodiimide, or the oxidized glycogenhexoses. The ribose, glucose and similar agents may penetrate the corneaeasily using drops, gel, or the slow release mechanisms, nanoparticle,microspares, liposome sets. In addition, the crosslinkers may bedelivered with Mucoadhesives.

In one or more embodiments, all or part of the donor cornea iscross-linked. Also, in one or more embodiments, a very highconcentration of Riboflavin may be used because the in vitrocross-linking process may be stopped whenever needed prior to thetransplantation of the donor cornea in the host eye. In addition, thepower of the ultraviolet (UV) laser may also be increased so as tocross-link the tissue of the donor cornea faster. The use of a highconcentration of Riboflavin, and the increasing of the ultraviolet (UV)laser power, are not possible during an in vivo cross-linking procedurebecause the aim of such an in vivo procedure is to protect the cells ofthe host cornea. Also, the in vivo process cannot be controlled asefficiently as in the vitro crosslinking of the corneal transplant.

In one or more embodiments, the donor cornea may be extracted from ahuman cadaver, or the cornea may be reconstructed as known in tissueengineering in vitro and three-dimensionally (3D) printed. Cross-linkingof a culture-grown cornea eliminates the cellular structure inside thecornea. If needed again, the healthy corneal endothelium of the patientmay be grown in vitro for these tissues by placing them on the concavesurface of the cornea and encouraging their growth under laboratorycontrol conditions prior to the transplantation.

In the embodiments where the donor cornea is tissue culture grown, thecornea may be formed from mesenchymal fibroblast stem cells, embryonicstem cells, or cells derived from epithelial stem cells extracted fromthe same patient, or a mixture of these cells. Using known tissueculture techniques, the cells may produce a transparent corneal stroma.This culture-grown corneal stroma will not have a corneal epithelium ora corneal endothelium. Thus, it eliminates the complexity of developinga full thickness cornea in the tissue culture. This stromal transplantmay be used as a lamellar or partial thickness replacement of theexisting host cornea. This transplant may also be used to augment or addto the thickness of the host cornea. This transparent corneal stroma maybe transplanted either prior to, or after being cross-linked usingvarious cross-linking methods.

In one or more embodiments, the cross-linked donor cornea may be sizedand precisely cut with a femtosecond laser to the desired shape andcurvature to replace the removed host cornea so that the refractiveerrors of the recipient are also automatically corrected with thecross-linked cornea.

Now, referring to FIG. 1C, it can be seen that the scarred and/ordiseased cornea 16 is shown being removed from the eye 10. The scarredand/or diseased cornea 16 may be removed from the eye 10 by usingvarious suitable means, such as mechanical means or cutting using alaser. When mechanical means are used to remove the scarred and/ordiseased cornea 16 from the eye 10, the scarred and/or diseased cornea16 may initially be cut away or dissected from the remainder of the eye10 using a sharp mechanical instrument (e.g., a surgical micro-knife, aneedle, a sharp spatula, a pair of micro-scissors), and thensubsequently removed or extracted with a pair of micro-forceps. Whenlaser cutting is used to remove the scarred and/or diseased cornea 16from the eye 10, the scarred and/or diseased cornea 16 may be cut awayusing a suitable laser, such as a femtosecond laser. Also, in someembodiments, the mechanical means for cutting and extraction (e.g., thesurgical micro-knife and/or pair of micro-scissors) may be used incombination with the laser means (e.g., the femtosecond laser).

In one or more embodiments, the donor cornea may be shaped and cut withthe femtosecond laser prior to the cross-linking thereof so as toreplace part or all of the recipient cornea which is cut with thefemtosecond laser. In these one or more embodiments, the entire donorand host cornea together may be cross-linked with Riboflavin and UVradiation. These procedures may also be performed on a culture-growntransplant cornea.

Then, as shown in FIG. 1D, after the scarred and/or diseased cornea 16has been removed from the eye 10, the cross-linked donor cornea 20 isimplanted into the eye 10 of the patient in the location previouslyoccupied by the scarred and/or diseased cornea 16. After implantation ofthe cross-linked donor cornea 20, sutures or a suitable adhesive may beutilized to secure the cross-linked donor cornea 20 in place on the eye10. When sutures are used for holding the donor cornea 20 in place, thesutures may comprise nylon sutures, steel sutures, or another suitabletype of non-absorbable suture. When the cornea 16 is subsequentlyablated after the implantation of the donor cornea, as will be describedhereinafter, additional sutures may be required after ablation.

In one or more embodiments, a biodegradable adhesive is used in acorneal transplantation procedure with the cross-linked donor cornea 20described above, or with a non-cross-linked corneal transplant. In theseone or more embodiments, the biodegradable adhesive obviates the needfor a suture in the corneal transplant procedure. Sutures generallydistort the surface of the cornea and can produce an opticallyunacceptable corneal surface. Also, the use of the biodegradableadhesive obviates the need for glues requiring exothermic energy. Gluesthat use an exothermic effect, such as Fibronectin, need thermal energyto activate their adhesive properties. This thermal energy, such as thatdelievered by a high-powered laser, produces sufficient heat tocoagulate the Fibronectin and the tissue that it contacts. Any thermaleffect on the cornea produces: (i) corneal opacity, (ii) tissuecontraction, and (iii) distortion of the optical surface of the cornea.The tissue adhesion created by these glues, including Fibronectin orfibrinogen, is flimsy and cannot withstand the intraocular pressure ofthe eye.

In fact, sutures are superior to these types of adhesives because thewound becomes immediately strong with sutures, thereby supporting thenormal intraocular pressure of between 18 and 35 mmHg. In contrast tothe use of a suture in which distortion that is caused by sutureplacement can be managed by cutting and removing the suture, thedistortion caused by the coagulated corneal tissue cannot be corrected.

Other glues, such as cyanoacrylate, become immediately solid aftercoming into contact with the tissue or water. These glues produce arock-hard polymer, the shape of which cannot be controlled afteradministration. Also, the surface of the polymer created by these gluesis not smooth. Thus, the eyelid will rub on this uneven surface, and theuneven surface scratches the undersurface of the eyelid when the eyelidmoves over it. In addition, the cyanoacrylate is not biodegradable orbiocompatible. As such, it causes an inflammatory response if applied tothe tissue, thereby causing undesirable cell migration andvascularization of the cornea.

Thus, by using a biocompatible and absorbable acrylate or otherbiodegradable glues that do not need exothermic energy for the processof adhesion (i.e., like fibronectin or fibrinogen), one is able tomaintain the integrity of the smooth corneal surface. In one or moreembodiments, the biocompatible and biodegradable adhesive may be paintedonly at the edges of the transplant prior to placing it in the host ordiseased cornea. In these embodiments, the biocompatible andbiodegradable adhesive only comes into contact with the host tissue atthe desired predetermined surface to create a strong adhesion. Theadhesion may last a few hours to several months depending on thecomposition of the molecule chosen and the concentration of the activecomponent.

Other suitable biodegradable adhesives or glues that may be used inconjunction with the transplant include combinations of gallic acid,gallic tannic acid, Chitosan, gelatin, polyphenyl compound, Tannic Acid(N-isopropylacrylamide (PNIPAM), and/or Poly(N-vinylpyrrolidone) withpolyethylene glycol (PEG). That is, polyethylene glycol (PEG) may bemixed with any one or plurality of gallic acid, gallic tannic acid,Chitosan, gelatin, polyphenyl compound, Tannic Acid(N-isopropylacrylamide (PNIPAM), and Poly(N-vinylpyrrolidone), so as toform a molecular glue. These adhesives are suitable for the use on thecornea because they create a tight wound that prevents leakage from thecorneal wound and maintain the normal intraocular pressure shortly aftertheir application and also do not distort the wound by causing tractionon the tissue.

In one or more embodiments, the donor cornea may be temporarily suturedto the host cornea by only a few single sutures to the host cornea.Then, the sutures may be removed immediately after donor cornea is fixedto the host cornea with a suitable adhesive.

A second illustrative embodiment of a corneal transplant procedure witha cross-linked cornea is shown in FIGS. 2A-2C. Unlike the firstembodiment described above, the corneal transplant procedure illustratedin FIGS. 2A-2C does not involve full corneal replacement of the scarredor diseased cornea by the donor cornea. Rather, FIGS. 2A-2C illustrate alamellar keratoplasty procedure wherein only a portion of the cornea 16′of the eye 10′ contains scarred and/or diseased tissue (i.e., afull-thickness corneal section is not removed). In the procedure ofFIGS. 2A-2C, an internal scarred and/or diseased portion 16 a′ of thecornea 16′ is externally removed from the eye 10′ of a patient.

Referring initially to FIG. 2A, it can be seen that only an internalportion 16 a′ of the cornea 16′ is scarred and/or diseased. As such, inthis embodiment, it is not necessary to replace the entire thickness ofthe cornea 16 with a donor cornea as was described above in conjunctionwith FIGS. 1A-1D, but rather just a portion of the cornea 16′.

Next, referring to FIG. 2B, it can be seen that the scarred and/ordiseased portion 16 a′ has been externally removed from the cornea 16′of the eye 10′ such that the cornea 16′ comprises a cavity 19 disposedtherein for receiving the donor cornea. Because an external approach wasutilized for removing the scarred and/or diseased portion 16 a′ of thecornea 16′, the cavity 19 comprises a notch-like void in the outside oranterior surface of the cornea 16′. As described above for the firstembodiment, the scarred and/or diseased corneal portion 16 a′ may beremoved from the remainder of the cornea 16′ using various suitablemeans, such as mechanical means or the laser cutting means (e.g.,femtosecond laser) described above.

Finally, as shown in FIG. 2C, after the scarred and/or diseased portion16 a′ has been removed from the remainder of the cornea 16′ of the eye10′, the cross-linked donor cornea or cross-linked donor corneal portion20′ is implanted into the eye 10′ of the patient in the locationpreviously occupied by the scarred and/or diseased corneal portion 16a′. As described above, after implantation of the cross-linked donorcorneal portion 20′ into the eye 10′, sutures or a suitable adhesive(e.g., the biocompatible and biodegradable adhesive described above) maybe utilized to secure the cross-linked donor corneal portion 20′ inplace on the host cornea of the eye 10′.

After the cross-linked donor corneal portion 20′ is implanted into theeye 10′ of the patient, a portion of the cornea 16′ may be ablated so asto change the refractive properties of the eye (e.g., to give thepatient perfect or near perfect refraction). The ablation of the portionof the cornea 16′ may be performed using a suitable laser 34, such as anexcimer laser. The ablation by the laser causes the ablated tissue toessentially evaporate into the air. Also, the ablation of the portion ofthe cornea 16′ may be done intrastromally, as with LASIK (laser-assistedin situ keratomileusis), or on the surface of the cornea, as with PRK(photorefractive keratectomy). The ablation may be performed apredetermined time period after the corneal transplantation so as toenable the wound healing process of the recipient's cornea to becompleted. It is to be understood that the ablation, which follows thecorneal transplantation, may be performed in conjunction with any of theembodiments described herein.

It is also to be understood that, in some alternative embodiments, theablation may be performed prior to the transplantation of the donorcornea, rather than after the transplantation of the donor cornea. Forexample, in one or more alternative embodiments, a lenticle may beprecisely cut in the tissue of a culture-grown stroma of a donor corneaby using a femtosecond laser so that when implanted into the hostcornea, it corrects the residual host eye's refractive error.

A third illustrative embodiment of a corneal transplant procedure with across-linked cornea is shown in FIGS. 3A-3C. Like the second embodimentdescribed above, the corneal transplant procedure illustrated in FIGS.3A-3C only involves replacing a scarred and/or diseased portion 16 a″ ofthe cornea 16″ with a donor corneal portion. Thus, similar to the secondembodiment explained above, FIGS. 3A-3C illustrate a lamellarkeratoplasty procedure wherein only a portion of the cornea 16″ of theeye 10″ contains scarred and/or diseased tissue (i.e., a full-thicknesscorneal section is not removed). Although, in the procedure of FIGS.3A-3C, an internal scarred and/or diseased portion 16 a″ of the cornea16″ is internally removed from the eye 10″ of a patient, rather thanbeing externally removed as in the second embodiment of FIGS. 2A-2C.

Referring initially to FIG. 3A, it can be seen that only an internalportion 16 a″ of the cornea 16″ of the eye 10″ is scarred and/ordiseased. As such, in this embodiment, like the preceding secondembodiment, it is not necessary to replace the entire thickness of thecornea 16″ with a donor cornea, but rather just a portion of the cornea16″.

Next, referring to FIG. 3B, it can be seen that the scarred and/ordiseased portion 16 a″ is being internally removed from the remainder ofthe cornea 16″ using a pair of forceps 22 (i.e., mechanical means ofremoval are illustrated in FIG. 3B). Advantageously, because an internalapproach is being utilized for removing the scarred and/or diseasedportion 16 a″ of the cornea 16″, the cornea 16″ will not comprise thenotch-like cavity 19 disposed in the outside or anterior surface of thecornea, which was described in conjunction with the preceding secondembodiment. As described above for the first and second embodiments, thescarred and/or diseased corneal portion 16 a″ may be removed from theremainder of the cornea 16″ using other suitable alternative means, suchas laser cutting techniques (e.g., using a femtosecond laser).Advantageously, the femtosecond laser is capable of cutting inside thetissue without involving the surface of the tissue. The cut part of thetissue can then be removed by other means (e.g., micro-forceps).

Finally, as shown in FIG. 3C, after the scarred and/or diseased cornealportion 16 a″ has been removed from the remainder of the cornea 16″ ofthe eye 10″, the cross-linked donor cornea or cross-linked donor cornealportion 20″ is implanted into the eye 10″ of the patient in the locationpreviously occupied by the scarred and/or diseased corneal portion 16a″. After implantation of the cross-linked donor corneal portion 20″,sutures or a suitable adhesive (e.g., the biocompatible andbiodegradable adhesive described above) may be utilized to secure thecross-linked donor corneal portion 20″ in place on the host cornea ofthe eye 10″. Advantageously, the cross-linked donor corneal portion 20″,which is strengthened by the cross-linking performed thereon, reinforcesthe cornea 16″ and greatly reduces the likelihood of corneal graftrejection.

It is to be understood that the scarred and/or diseased corneal portion16 a″ that is removed from the cornea 16″ may also be replaced withstroma stem cells or mesenchymal stem cells, which can be contained in amedium, and then injected in the internal cavity previously occupied bythe scarred and/or diseased corneal tissue 16 a″.

In one or more embodiments, mesenchymal stem cells also may be injectedinside the donor cornea before or after transplantation. In addition, inone or more embodiments, daily drops of a Rho Kinase inhibitor may beadded to the host eye after the surgery. The use of a medication, suchas a Rho Kinase inhibitor, with the stem cells will encourage stem cellproliferation.

A fourth illustrative embodiment of a corneal transplant procedure witha cross-linked cornea is shown in FIGS. 4A-4E. Like the second and thirdembodiments described above, the corneal transplant procedureillustrated in FIGS. 4A-4E only involves replacing a scarred and/ordiseased portion 16 a′″ of the cornea 16′″ with a donor corneal portion.Thus, similar to the second and third embodiments explained above, FIGS.4A-4E illustrate a lamellar keratoplasty procedure wherein only aportion of the cornea 16′″ of the eye 10′″ contains scarred and/ordiseased tissue (i.e., a full-thickness corneal section is not removed).Although, in the procedure of FIGS. 4A-4E, a different-shaped scarredand/or diseased portion 16 a′″ of the cornea 16′″ is removed.

Referring initially to FIG. 4A, it can be seen that only a portion 16a′″ of the cornea 16′″ having a T-shape or “top hut” shape is scarredand/or diseased. As such, in this embodiment, it is not necessary toreplace the entire thickness of the cornea 16′″ with a donor cornea aswas described above in conjunction with FIGS. 1A-1D, but rather just aportion 16 a′″ of the cornea 16′″. In this illustrative embodiment, theback side of the cornea 16′″ is maintained (see e.g., FIG. 4D).

In FIG. 4B, the cross-linking 18′ of the clear donor cornea 20′ isdiagrammatically illustrated. As mentioned above, it is to be understoodthat all or just a part of the donor cornea 20′ may be cross-linked.Then, in FIG. 4C, it can be seen that a portion 20 a′ of the clear donorcornea 20′, which has a T-shape or “top hut” shape that matches theshape of the scarred and/or diseased portion 16 a′″ of the cornea 16′″,is cut out from the remainder of the clear donor cornea 20′ such that ithas the necessary shape. In one or more embodiments, the portion 20 a′may be cut from the clear donor cornea 20′ and appropriately shapedusing a femtosecond laser. As shown in FIGS. 5A and 5B, other suitablyshaped cross-linked corneal portions may be cut from the clear donorcornea 20′, such as a dumbbell-shaped corneal portion 20 a″ (see FIG.5A) or a corneal portion 20 a′″ having a reversed T-shape or “reversedtop hut” shape (see FIG. 5B), in order to accommodate correspondinglyshaped scarred and/or diseased areas in the host cornea.

Next, referring to FIG. 4D, it can be seen that the scarred and/ordiseased portion 16 a′″ having the T-shape or “top hut” shape has beenremoved from the cornea 16′″ of the eye 10′″ such that the cornea 16′″comprises a cavity 19′ disposed therein for receiving the donor cornea.As described above for the first three embodiments, the scarred and/ordiseased corneal portion 16 a′″ may be removed from the remainder of thecornea 16′″ using various suitable means, such as mechanical means orthe laser cutting means (e.g., femtosecond laser) described above.

Finally, as shown in FIG. 4E, after the scarred and/or diseased portion16 a′″ has been removed from the remainder of the cornea 16′″ of the eye10′″, the cross-linked donor corneal portion 20 a′ is implanted into theeye 10′″ of the patient in the location previously occupied by thescarred and/or diseased corneal portion 16 a′″. Because the shape of thetransplant corresponds to that of the removed portion 16 a′″ of thecornea 16′″, the transplant sits comfortably in its position in the hostcornea. As described above, after implantation of the cross-linked donorcorneal portion 20 a′ into the eye 10′″, sutures or a suitable adhesive(e.g., the biocompatible and biodegradable adhesive described above) maybe utilized to secure the cross-linked donor corneal portion 20 a′ inplace on the host cornea 16′″ of the eye 10′″. For example, if abiocompatible and biodegradable adhesive is used to secure thecross-linked donor corneal portion 20 a′ in place in the cornea 16′″ ofthe eye 10′″, the edges of the donor corneal portion 20 a′ are coatedwith the biocompatible and biodegradable adhesive so as to give thetransplant a reliable stability. In this case, it is desirable to havethe attachment of the transplant maintained by the biocompatible andbiodegradable adhesive for a period of months (i.e., it is desirable forthe transplant to be secured in place by the biocompatible andbiodegradable adhesive for as long as possible).

An illustrative embodiment of a corneal lenslet implantation procedurewith a cross-linked cornea is shown in FIGS. 6A-6C and 7A-7C. Similar tothe second, third, and fourth embodiments described above, FIGS. 6A-6Cand 7A-7C illustrate a lamellar keratoplasty procedure wherein only aportion of the cornea 16″″ of the host eye 10″″ is removed during theprocedure (i.e., a full-thickness corneal section is not removed).Although, the procedure of FIGS. 6A-6C and 7A-7C differs in severalimportant respects from the abovedescribed procedures. In thisembodiment, the corneal transplant is cross-linked in vitro. Then, usinga femtosecond laser or an excimer laser, the surgeon carves out orablates a three-dimensional (3D) corneal cross-linked augment from thedonor cornea 20′″ that exactly compensates for the refractive error ofthe recipient of the transplant. That is, the corneal cross-linkedaugment or inlay may be cut to the desired shape using a femtosecondlaser, or the inlay may be shaped in vitro using an excimer laser priorto its implantation in the cornea 16″″ of the host eye 10″″. Aftermaking an internal pocket 28 in the recipient cornea 16″″ of the hosteye 10″″ with a femtosecond laser, the cross-linked transplant is foldedand implanted in a predetermined fashion inside the host's cornealpocket 28 to provide stability to the eye 10″″ having keratoconus,keratoglobus, a thin cornea or abnormal corneal curvature, therebypreventing future corneal ectasia in this eye 10″″ and correcting itsrefractive errors. Advantageously, the procedure of this embodimentcomprises a lamellar cross-linked corneal transplantation, whichadditionally results in simultaneous correction of the refractive errorof the eye 10″″ of the patient. As used herein, the term “lenslet”refers to a lens implant configured to be implanted in a cornea of aneye. The lens implant may be formed from an organic material, asynthetic material, or a combination of organic and synthetic materials.

Now, with reference to FIGS. 6A-6C and 7A-7C, the illustrativeembodiment will be described in further detail. The host eye 10″″ withlens 12′, cornea 16″″, and optic nerve 24 is shown in FIG. 6A, while thedonor cornea 20′″ is depicted in FIG. 7A. The donor cornea 20′″ of FIG.7A may be a cross-linked cornea of a cadaver or a tissue culture-growncornea that has been cross-linked. Turning to FIG. 6B, it can be seenthat an internal corneal pocket 28 is created in the cornea 16″″ of thehost eye 10″″ (e.g., by using a suitable laser, which is indicateddiagrammatically in FIG. 6B by lines 30).

In FIG. 7A, the cross-linking 18″ of the donor cornea 20′″ isdiagrammatically illustrated. As mentioned in the preceding embodiments,it is to be understood that all or just a part of the donor cornea 20′″may be cross-linked. Then, after the donor cornea 20′″ of FIG. 7A hasbeen cross-linked (e.g., by using a photosensitizer in the form ofriboflavin and UV radiation as described above), it can be seen that across-linked lamellar lenslet 26 is cut out from the remainder of thedonor cornea 20′″ (e.g., by using a suitable laser, which is indicateddiagrammatically in FIG. 7B by lines 32) such that it has the necessaryshape for implantation into the host eye 10″″. As explained above, thecross-linked lamellar lenslet 26 may be cut from the donor cornea 20′″and appropriately shaped using a femtosecond laser or an excimer laser.The cross-linked lamellar lenslet 26 is capable of being prepared to anyrequisite shape using either the femtosecond laser or the excimer laser.FIG. 7C illustrates the shaped cross-linked lamellar lenslet 26 after ithas been removed from the remainder of the donor cornea 20′″.

Finally, as shown in FIG. 6C, the cross-linked lamellar lenslet 26 isimplanted into the cornea 16″″ of the host eye 10″″ of the patient inthe location where the pocket 28 was previously formed. Because theshape of the transplant corresponds to that of the pocket 28 formed inthe eye 10″″, the transplant sits comfortably in its position in thehost cornea 16″″. As described above, after implantation of thecross-linked lamellar lenslet 26 into the eye 10″″, the refractiveerrors of the eye 10″″ have been corrected because the cross-linkedlamellar lenslet 26 has been appropriately shaped to compensate for thespecific refractive errors of the host eye 10″″ prior to itsimplantation into the eye 10″″. In addition, as explained above, theimplantation of the cross-linked lamellar lenslet 26 provides additionalstability to an eye having keratoconus, keratoglobus, a thin cornea, orabnormal corneal curvature.

Another illustrative embodiment of a corneal lenslet implantationprocedure with a cross-linked cornea is shown in FIGS. 8-14. In general,the procedure illustrated in these figures involves forming atwo-dimensional cut into a cornea of an eye; creating athree-dimensional pocket in the cornea of the eye, cross-linking theinterior stroma, and inserting a lenslet or lens implant into thethree-dimensional pocket after the internal stromal tissue has beencross-linked.

Initially, in FIG. 8, the forming of a two-dimensional cut 115 into thecornea 112 of the eye 110 is diagrammatically illustrated. Inparticular, as shown in the illustrative embodiment of FIG. 8, thetwo-dimensional cut 115 is formed by making an intrastromal incision inthe cornea 112 of the eye 110 using a femtosecond laser (i.e., theincision is cut in the cornea 112 using the laser beam(s) 114 emittedfrom the femtosecond laser). Alternatively, the two-dimensional cut 115may be formed in the cornea 112 of the eye 110 using a knife.

Then, in FIG. 9, the forming of a three-dimensional corneal pocket 116in the cornea 112 of the eye 110 is diagrammatically illustrated. Inparticular, as shown in the illustrative embodiment of FIG. 9, thethree-dimensional corneal pocket 116 is formed by using a spatula 118.The formation of the intracorneal pocket 116 in the cornea 112 of theeye 110 allows one to gain access to the tissue surrounding the pocket116 (i.e., the interior stromal tissue surrounding the pocket 116).

Turning again to FIGS. 8 and 9, in the illustrative embodiment, thecorneal pocket 116 formed in the cornea 112 of the eye 110 may be in theform of an intrastromal corneal pocket cut into the corneal stroma. Afemtosecond laser may be used to form a 2-dimensional cut into thecornea 112, which is then opened with a spatula 118 to create a3-dimensional pocket 116. In one embodiment, a piece of the cornea 112or a cornea which has a scar tissue is first cut with the femtosecondlaser. Then, the cavity is cross-linked before filling it with animplant or inlay 128 to replace the lost tissue with a clear flexibleinlay or implant 128 (see FIG. 12).

In one embodiment, a three-dimensional (3D) uniform circular, oval, orsquared-shaped corneal pocket 116 is cut with a femtosecond laser andthe tissue inside the pocket is removed to produce a three-dimensional(3D) pocket 116 to be cross-linked with riboflavin and implanted with aprepared implant.

After the pocket 116 is formed using the spatula 118, a photosensitizeris applied inside the three-dimensional pocket 116 so that thephotosensitizer permeates the tissue surrounding the pocket 116 (seeFIG. 10). The photosensitizer facilitates the cross-linking of thetissue surrounding the pocket 116. In the illustrative embodiment, thephotosensitizer is injected with a needle 120 inside the stromal pocket116 without lifting the anterior corneal stroma so as to cover theinternal surface of the corneal pocket 116. In one or more embodiments,the photosensitizer or cross-linker that is injected through the needle120 inside the stromal pocket comprises riboflavin, and/or a liquidsuspension having nanoparticles of riboflavin disposed therein.Preferably, the cross-linker has between about 0.1% riboflavin to about100% riboflavin therein (or between 0.1% and 100% riboflavin therein).Also, in one or more embodiments, an excess portion of thephotosensitizer in the pocket 116 may be aspirated through the needle120 until all, or substantially all, of the excess portion of thephotosensitizer is removed from the pocket 116 (i.e., the excesscross-linker may be aspirated through the same needle so that the pocket116 may be completely emptied or substantially emptied).

Next, turning to the illustrative embodiment of FIG. 11A, shortly afterthe photosensitizer is applied inside the pocket 116, the cornea 112 ofthe eye 110 is irradiated from the outside using ultraviolet (UV)radiation 122 so as to activate cross-linkers in the portion of thetissue surrounding the three-dimensional pocket 116, and thereby stiffenthe cornea 112, prevent corneal ectasia of the cornea 112, and killcells in the portion of the tissue surrounding the pocket 116. In theillustrative embodiment, the ultraviolet light used to irradiate thecornea 112 may have a wavelength between about 370 nanometers and about380 nanometers (or between 370 nanometers and 380 nanometers). Also, inthe illustrative embodiment, only a predetermined anterior stromalportion 124 of the cornea 112 to which the photosensitizer was appliedis cross-linked (i.e., the surrounding wall of the corneal pocket 116),thereby leaving an anterior portion of the cornea 112 and a posteriorstromal portion of the cornea 112 uncross-linked. That is, in theillustrative embodiment, the entire corneal area inside the cornea 112exposed to the cross-linker is selectively cross-linked, thereby leavingthe anterior part of the cornea 112 and the posterior part of the stromauncross-linked. The portion of the cornea 112 without the cross-linkeris not cross-linked when exposed to the UV radiation. In an alternativeembodiment, the cornea 112 may be irradiated using wavelengths of lightother than UV light as an alternative to, or in addition to beingirradiated using the ultraviolet (UV) radiation 122 depicted in FIG.11A. Also, microwave radiation may be used synergistically or additivelyto correct non-invasively the remaining refractive error(s) of thecornea.

Alternatively, as shown in FIG. 11B, a fiber optic 126 may be insertedinto the corneal pocket 116 so as to apply the ultraviolet radiation andactivate the photosensitizer in the wall of the corneal pocket 116. Whenthe fiber optic 126 is used to irradiate the wall of the pocket 116, theultraviolet radiation is applied internally, rather than externally asdepicted in FIG. 11A.

Now, with reference to FIG. 12, it can be seen that, after the wall ofthe corneal pocket 116 has been stiffened and is devoid of cellularelements by the activation of the cross-linkers, a lens implant 128 isinserted into the corneal pocket 116 in order to change the refractiveproperties of the eye. In particular, in the illustrated embodiment, thelens implant 128 is inserted through a small incision, and into thecorneal pocket 116, using forceps or microforceps. In one or moreembodiments, the lens implant 128 that is inserted inside the pocket 116in the cornea 112 is flexible and porous. Also, in one or moreembodiments, the lens implant 128 may comprise a hybrid lens implantwith an organic outer portion and a synthetic inner portion. The organicouter portion of the hybrid lens implant may be made from a transparent,hydrophilic organic polymer, while the synthetic inner portion of thehybrid lens implant may be made from a transparent, gas permeable,porous flexible polymer. For example, the transparent, hydrophilicpolymer forming the organic outer portion may be formed from collagen,chitosan, poloxamer, polyethylene glycol, or a combination thereof (orany other transparent hydrophilic coating which can be deposited overthe entire lens surface), while the flexible polymer forming thesynthetic inner portion of the hybrid lens implant may be formed fromsilicone, acrylic, polymetacrylate, hydrogel, or a combination thereof.The surface of the lens implant 128 may have the appropriate shape toreshape the cornea 112 or the dioptric power to nullify the remainingspheric or astigmatic error of the eye. More particularly, in one ormore embodiments, the lens implant 128 may have one of: (i) a concavesurface to correct myopic refractive errors (i.e., a minus lens forcorrecting nearsightedness), (ii) a convex surface to correct hyperopicrefractive errors (i.e., a plus lens for correcting farsightedness), or(iii) a toric shape to correct astigmatic refractive errors.

In the illustrative embodiment, the irradiation of the cornea 112 usingthe ultraviolet (UV) radiation 122 only activates cross-linkers in theportion of the stromal tissue surrounding the three-dimensional pocket116, and only kills the cells in the portion of the tissue surroundingthe pocket 116, so as to leave only a thin layer of cross-linkedcollagen to prevent an immune response and rejection of the lens implant128 and/or encapsulation by fibrocytes, while preventing post-operativedry eye formation. In addition to preventing encapsulation of the lensimplant 128 by fibrocytes, the cross-linking of the stromal tissuesurrounding the pocket 116 also advantageously prevents corneal hazeformation around the lens implant 128. That is, the cross-linking of thestromal tissue surrounding the lens implant 128 prevents formation ofmyofibroblast from surrounding keratocytes, which then convert graduallyto fibrocytes that appear as a haze, and then white encapsulation insidethe cornea, thereby causing light scattering in front of the patient'seye.

As shown in FIGS. 13 and 14, the crosslinking procedure described abovemay be repeated after the lens implant 128 is implanted so as to preventany cellular invasion in the area surrounding the implant 128.Initially, with reference to FIG. 13, the photosensitizer is reinjectedinside the space between the lens implant 128 and the surroundingcorneal tissue using a needle 120. In one or more embodiments, theneedle 120 for injecting the photosensitizer may comprise a 30-32 gaugeneedle. Then, after the reinjection of the cross-linker, the cornea 112is re-irradiated with ultraviolet radiation 122 to cross-link the tissuesurrounding the lens implant 128 so as to prevent cellular migrationtowards the lens implant 128 (see FIG. 14).

In one or more embodiments, the lens implant or inlay 128 may beprepared ahead of time with known techniques, wherein the inlay 128 maybe coated with a biocompatible material, such as collagen, elastin,polyethylene glycol, biotin, streptavidin, etc., or a combinationthereof. The inlay 128 and the coating may be cross-linked with aphotosensitizer or cross-linker, such as riboflavin, prior to beingimplanted into the pocket 116 in the cornea 112 of the eye.

In another embodiment, the lens implant or inlay 128 may be silicone,methacrylate, hydroxyethylmethacrylate (HEMA), or any otherbiocompatible transparent material, or a mixture thereof. The lensimplant or inlay 128 also may be coated with materials, such as collagenor elastin, and may have a desired thickness of from 2 microns to 70microns or more.

In yet another embodiment, the lens implant or inlay 128 is formed froman eye bank cornea, or a cross-linked eye bank cornea, etc. In general,there is a tremendous paucity of normal cadaver corneas for total orpartial implants, such as for a corneal transplant of a corneal inlay.Because all the cellular elements are killed during the crosslinking ofthe corneal inlay, and because the corneal collagen is cross-linked anddenatured, the remaining collagenous elements are not immunogenic whenimplanted inside the body or in the cornea of a patient. Advantageously,the prior cross-linking of the organic material, such as in the cadavercornea, permits transplantation of the corneal inlay from an animal orhuman cornea or any species of animal to another animal or human for thefirst time without inciting a cellular or humoral response by the body,which rejects the inlay. Thus, cross-linking transparent cadaverictissue for corneal transplantation, or as an inlay to modify of therefractive power of the eye, is highly beneficial to many patients whoare on the waiting list for a corneal surgery. In addition, the surgerymay be planned ahead of time without necessitating the urgency of thesurgery when a fresh cadaver eye becomes available. In one or moreembodiments, the collagens may be driven from the animal cornea, andcross-linked. Also, in one or more embodiments, the implant or inlay 128may be made of cross-linked animal cornea or human cornea that is cutusing a femtosecond laser to any desired shape and size, and thenablated with an excimer laser or cut with a femtosecond laser to a havea desired refractive power.

For example, as shown in FIG. 15, the lens implant or inlay 130 may beformed from an organic block of a polymer (e.g., donor cornea) bycutting the lens implant 130 using an excimer laser (e.g., by using thelaser beam(s) 132 emitted from the excimer laser). Alternatively,referring to FIG. 16, the lens implant or inlay 130′ may be formed froman organic block 134 of a polymer (e.g., donor cornea) by cutting thelens implant 130′ from the block 134 using a femtosecond laser or acomputerized femto-system (e.g., by using the laser beam(s) 136 emittedfrom the femtosecond laser).

In still another embodiment, as depicted in FIG. 17, the lens implant orinlay 130″ is made using three-dimensional (3D) printing technology or amolding technique in order to form the lens implant or inlay 130″ intothe desired shape, size or thickness. The transparent material of the3D-printed implant or inlay 130″ may be coated with one or morebiocompatible polymers and cross-linked prior to the implantation.

In yet another embodiment, after the implantation of an intraocularlens, the remaining refractive error of the eye may be corrected by theimplantation of a lens implant or inlay 128 in the cross-linked pocket116 of the cornea 112, thereby eliminating the need for entering the eyecavity to replace the original intraocular lens.

In still another embodiment, the remaining refractive error of the eyeis corrected after an intraocular lens implantation by placing an inlay128 on the surface of the cornea 112 of the patient while the shape ofthe cornea 112 is corrected with an excimer laser and wavefrontoptimized technology so that the patient is provided instant input onits effect on his or her vision. In this embodiment, an inlay similar toa contact lens is placed on the cornea 112 that, after correction,matches the desired refractive correction of the eye, and then,subsequently, the inlay 128 is implanted inside the cross-linked cornealpocket 116.

In yet another embodiment, the implant or inlay 128 may be ablated withan excimer laser for implantation in the cross-linked pocket 116, orafter cross-linking the exposed corneal stroma in LASIK surgery.

In still another embodiment, a small amount of hyaluronic acid or aviscous fluid is injected into the pocket 116 prior to the implantationof the implant or inlay 128 so as to simplify the insertion of theimplant or inlay 128 in the corneal pocket 116.

In yet another embodiment, the implant or inlay 128 is prepared havingfour marking holes of 0.1-2 millimeter (mm) in diameter in the inlayperiphery at an equally sized distances so that the implant 128 may berotated with a hook, if desired, after the implantation as needed tomatch the axis of an astigmatic error of the eye during the surgery asmeasured simultaneously with a wavefront technology system, such as anOptiwave Refractive Analysis (ORA) system or Holos® system, which arecommercially available for measurement of astigmatism or its axis.

In still another embodiment, the implant or inlay 128 is located on thevisual axis and may provide 1 to 3 times magnification for patientswhose macula is affected by a disease process needing magnifying glassesfor reading, such as in age-related macular degeneration, macular edema,degenerative diseases of the retina, etc. Because these eyes cannot beused normally for reading without external magnifier glasses, providingmagnification by a corneal implant to one eye assists the patients inbeing able to read with one eye and navigate the familiar environmentwith their other eye.

In yet another embodiment, the surface of the cornea 112 is treatedafter surgery in all cases daily with an anti-inflammatory agent, suchas steroids, nonsteriodal anti-inflammatory drugs (NSAIDs),immune-suppressants, such as cyclosporine A or mycophenolic acid,anti-proliferative agents, antimetabolite agents, or anti-inflammatoryagents (e.g., steroids, NSAIDS, or antibiotics etc.) to preventinflammatory processes after the corneal surgery, inlay implantation orcrosslinking, while stabilizing the integrity of the implant 128 andpreventing future cell growth in the organic implant or the adjacentacellular corneal tissue. In this embodiment, the medication is injectedin the corneal pocket 116 along with the implantation or the implant 128is dipped in the medication first, and then implanted in thecross-linked corneal pocket 116.

In still another embodiment, a cross-linked corneal inlay is placed overthe cross-linked corneal stroma after a LASIK incision, and is abated tothe desired size with an excimer laser using a topography guidedablation. By means of this procedure, the refractive power of the eye iscorrected, while simultaneously providing stability to an eye prone toconceal ectasia postoperatively after a LASIK surgery. Then, the LASIKflap is placed back over the implant.

Yet another illustrative embodiment of a corneal lenslet implantationprocedure with a cross-linked cornea is shown in FIGS. 18-23. Ingeneral, the procedure illustrated in these figures involves initiallymaking an intrastromal square pocket surrounding the visual axis of theeye, and then, after forming the initial square pocket, athree-dimensional circular portion of diseased or weak stromal tissue iscut, removed, and replaced with a circular implant which fits into thecircle that borders the four sides of the square. A front view of thecornea 212 of the eye 210 with the centrally-located visual axis 214 isillustrated in FIG. 18. Advantageously, in the illustrative embodimentof FIGS. 18-23, corneal tissue removal around the visual axis is greatlyfacilitated, and nearly perfect centration of the lens implant or inlay220 about the visual axis is possible because the lens implant 220 fitswithin a depressed circular recess at the bottom of the pocket 216. Assuch, the undesirable decentering of the lens implant is prevented.

Initially, in FIG. 19, the forming of an intrastromal square-shapedpocket 216 surrounding the visual axis 214 (represented by a plus sign)in the cornea 212 of the eye 210 is diagrammatically illustrated. Inparticular, as shown in the illustrative embodiment of FIG. 19, thesquare-shaped pocket 216 is formed by making a two-dimensionalintrastromal incision in the cornea 212 of the eye 210 using afemtosecond laser (i.e., the incision is cut in the cornea 212 using thelaser beam(s) emitted from the femtosecond laser).

Then, in FIG. 20, the removal of a three-dimensional circular portion218 of diseased or weak stromal tissue in the cornea 212 of the eye 210is diagrammatically illustrated. In particular, as shown in theillustrative embodiment of FIG. 20, the three-dimensional circularstromal tissue portion 218 has a first diameter, which is less than awidth of the square-shaped pocket 216 so that the three-dimensionalcircular stromal tissue portion 218 is disposed within the boundaries ofthe square-shaped pocket 216. The three-dimensional circular stromaltissue portion 218′ depicted in FIG. 21 is generally similar to thatillustrated in FIG. 20, except that the three-dimensional circularstromal tissue portion 218′ depicted in FIG. 21 has a second diameterthat is slightly larger than the first diameter of the three-dimensionalcircular stromal tissue portion 218 in FIG. 20. As such, the peripheryof the three-dimensional circular stromal tissue portion 218′ depictedin FIG. 21 is disposed closer to the square-shaped pocket 216, but stillwithin the confines of the square-shaped pocket 216. In the illustrativeembodiment, the three-dimensional circular stromal tissue portion 218,218′ may be removed using forceps or micro-forceps. In an exemplaryembodiment, the diameter of the circular stromal tissue portion 218,218′ that is removed from the cornea 212 is between approximately 5millimeters and approximately 8 millimeters, inclusive (or between 5millimeters and 8 millimeters, inclusive).

In an alternative embodiment of the corneal lenslet implantationprocedure, three (3) sequential cuts may be made in the stromal portionof the cornea 212 of the eye 210 using a femtosecond laser in order toform the pocket. First, a lower circular cut or incision centered aboutthe visual axis (i.e., a lower incision with the patient in a supineposition) is made using the femtosecond laser. Then, a second verticalcut is made above the lower incision using the femtosecond laser to formthe side(s) of a circular cutout portion. Finally, a third square orcircular cut (i.e., an upper incision) is made above the vertical cutusing the femtosecond laser. In the illustrative embodiment, the lowerincision is parallel to the upper incision, and the vertical cut extendsbetween lower incision and the upper incision. In this alternativeembodiment, the three-dimensional circular stromal tissue cutout portionbounded by the lower incision on the bottom thereof, the vertical cut onthe side(s) thereof, and the upper incision on the top thereof isremoved from the cornea 212 of the eye 210 using a pair of forceps. Acavity formed by the upper incision facilitates the removal of thethree-dimensional circular stromal tissue cutout portion. As describedabove, the third cut or incision formed using the femtosecond laser maybe an upper circular cut that is larger than the lower circular cut,rather than an upper square cut that is larger than the lower circularcut.

Turning to FIG. 22, after the three-dimensional circular stromal tissueportion 218, 218′ is removed, a photosensitizer is applied inside thepocket 216 so that the photosensitizer permeates the tissue surroundingthe pocket 216. The photosensitizer facilitates the cross-linking of thetissue surrounding the pocket 216. In the illustrative embodiment, thephotosensitizer is injected with a needle 222 inside the stromal pocket216. In one or more embodiments, the photosensitizer or cross-linkerthat is injected through the needle 222 inside the stromal pocket 216comprises riboflavin, and/or a liquid suspension having nanoparticles ofriboflavin disposed therein. Preferably, the cross-linker has betweenabout 0.1% riboflavin to about 100% riboflavin therein (or between 0.1%and 100% riboflavin therein). Also, in one or more embodiments, anexcess portion of the photosensitizer in the pocket 216 may be aspiratedthrough the needle 222 until all, or substantially all, of the excessportion of the photosensitizer is removed from the pocket 216 (i.e., theexcess cross-linker may be aspirated through the same needle 222 so thatthe pocket 216 may be completely emptied or substantially emptied).

Next, turning again to the illustrative embodiment of FIG. 22, shortlyafter the photosensitizer is applied inside the pocket 216, the cornea212 of the eye 210 is irradiated from the outside using ultraviolet (UV)radiation 224 so as to activate cross-linkers in the portion of thetissue surrounding the three-dimensional pocket 216, and thereby stiffenthe cornea 212, prevent corneal ectasia of the cornea 212, and killcells in the portion of the tissue surrounding the pocket 216. In theillustrative embodiment, the ultraviolet light used to irradiate thecornea 212 may have a wavelength between about 370 nanometers and about380 nanometers (or between 370 nanometers and 380 nanometers). Also, inthe illustrative embodiment, only a predetermined anterior stromalportion of the cornea 212 to which the photosensitizer was applied iscross-linked (i.e., the surrounding wall of the corneal pocket 216),thereby leaving an anterior portion of the cornea 212 and a posteriorstromal portion of the cornea 212 uncross-linked. That is, in theillustrative embodiment, the entire corneal area inside the cornea 212exposed to the cross-linker is selectively cross-linked, thereby leavingthe anterior part of the cornea 212 and the posterior part of the stromauncross-linked. The portion of the cornea 212 without the cross-linkeris not cross-linked when exposed to the UV radiation. In an alternativeembodiment, the cornea 212 may be irradiated using wavelengths of lightother than UV light as an alternative to, or in addition to beingirradiated using the ultraviolet (UV) radiation 224 depicted in FIG. 22.Also, microwave radiation may be used synergistically or additively tocorrect non-invasively the remaining refractive error(s) of the cornea.In addition, in an alternative embodiment, the ultraviolet (UV)radiation may be applied after the implantation of the lens implant 220to perform the crosslinking, rather than before the implantation of thelens implant 220 as described above. Further, rather than applying theultraviolet (UV) radiation from outside the cornea 212, the stromaltissue of the pocket 216 may be irradiated from inside by means of afiber optic, before or after the implantation of the lens implant 220.

Now, with combined reference to FIGS. 22 and 23, it can be seen that,before or after the wall of the corneal pocket 216 has been stiffenedand is devoid of cellular elements by the activation of thecross-linkers, a circular lens implant 220 is inserted into the circularrecess at the bottom of the pocket 216 formed by the three-dimensionalcircular stromal tissue cutout portion 218, 218′ that was removed. Thatis, the circular lens implant 220 fits within the periphery of thecircular recess that borders the four sides of the squared-shaped pocket216. In particular, in the illustrated embodiment, the circular lensimplant 220 is inserted through a small incision, and into the circularrecess at the bottom of the pocket 216 using forceps or microforceps. Inthe illustrative embodiment, the flexible lens implant 220 may befolded, inserted through the small incision, placed inside the circularrecess at the bottom of the pocket 216, and finally unfolded throughthen small incision. In one or more embodiments, the lens implant 220that is inserted inside the pocket 216 in the cornea 212 is flexible andporous. Also, in one or more embodiments, the lens implant 220 maycomprise a hybrid lens implant with an organic outer portion and asynthetic inner portion. The organic outer portion of the hybrid lensimplant may be made from a transparent, hydrophilic organic polymer,while the synthetic inner portion of the hybrid lens implant may be madefrom a transparent, gas permeable, porous flexible polymer. For example,the transparent, hydrophilic polymer forming the organic outer portionmay be formed from collagen, chitosan, poloxamer, polyethylene glycol,or a combination thereof (or any other transparent hydrophilic coatingwhich can be deposited over the entire lens surface), while the flexiblepolymer forming the synthetic inner portion of the hybrid lens implantmay be formed from silicone, acrylic, polymetacrylate, hydrogel, or acombination thereof.

Advantageously, the lens implant 220 of the aforedescribed illustrativeembodiment always remains perfectly centered around the visual axis 214of the eye 210, and will not move because it is disposed within thecircular recess at the bottom of the pocket 216. As explained above, thelens implant 220 may be formed from an organic material, syntheticmaterial, polymeric material, and combinations thereof. The lens implant220 may replace either a diseased tissue or create a new refractivepower for the eye 210, as explained hereinafter.

In the illustrative embodiment, the lens implant 220 may correct therefractive errors of the eye 210. The refractive error correction may bedone by the lens implant 220 having a curvature that changes the cornealsurface of the cornea 212. Alternatively, the lens implant 220 may havea different index of refraction that corrects the refractive power ofthe cornea 212. In the illustrative embodiment, the lens implant 220 mayhave the appropriate shape to reshape the cornea 212 or the dioptricpower to nullify the remaining spheric or astigmatic error of the eye.More particularly, in one or more embodiments, the lens implant 220 mayhave one of: (i) a concave anterior surface to correct myopic refractiveerrors (i.e., a minus lens for correcting nearsightedness), (ii) aconvex anterior surface to correct hyperopic refractive errors (i.e., aplus lens for correcting farsightedness), or (iii) a toric shape tocorrect astigmatic refractive errors.

In the illustrative embodiment, the irradiation of the cornea 212 usingthe ultraviolet (UV) radiation 224 only activates cross-linkers in theportion of the stromal tissue surrounding the three-dimensional pocket216, and only kills the cells in the portion of the tissue surroundingthe pocket 216, so as to leave only a thin layer of cross-linkedcollagen to prevent an immune response and rejection of the lens implant220 and/or encapsulation by fibrocytes, while preventing post-operativedry eye formation. In addition to preventing encapsulation of the lensimplant 220 by fibrocytes, the cross-linking of the stromal tissuesurrounding the pocket 216 also advantageously prevents corneal hazeformation around the lens implant 220. That is, the cross-linking of thestromal tissue surrounding the lens implant 220 prevents formation ofmyofibroblast from surrounding keratocytes, which then convert graduallyto fibrocytes that appear as a haze, and then white encapsulation insidethe cornea, thereby causing light scattering in front of the patient'seye.

It is readily apparent that the aforedescribed corneal transplantprocedures offer numerous advantages. First, the implementation of theaforedescribed corneal transplant procedures reduces the likelihood thatthe implanted cornea will be rejected by the patient. Secondly, theaforedescribed corneal transplant procedures enable the clarity of thetransplanted cornea to be preserved. Finally, the aforedescribed cornealtransplant procedures reduce the likelihood that the transplanted corneawill be invaded by migrating cells, such as migrating cells that mightinitiate an immune response such as macrophage, lymphocytes orleucocytes or vascular endothelial cells. These types of migrating cellsare discouraged by the cross-linked corneal collagen which does notprovide an easily accessible tissue to invade. In addition, the use ofabovedescribed tissue adhesives reduces the surgical proceduresignificantly. Moreover, the aforedescribed corneal lenslet implantationprocedures modify the cornea so as to better correct ametropicconditions. Furthermore, the corneal lenslet implantation proceduresdescribed above prevent the lens implant from moving around inside thecornea once implanted, thereby ensuring that the lens implant remainscentered about the visual axis of the eye.

With reference to the embodiment of FIGS. 24A-27B, a first illustrativeintracorneal lens implantation procedure with a cross-linked cornea willbe explained. In general, the procedure illustrated in these figuresinvolves forming a pocket in the cornea of an eye, cross-linking theinterior stroma, inserting a lens implant into the pocket, and thenapplying laser energy to the lens implant in the pocket using a laser tocorrect refractive errors of the lens implant and/or the eye in anon-invasive manner. In this embodiment, no flap is formed in the cornea300 of the eye.

In FIGS. 24A and 24B, the forming of a corneal pocket 302 in the cornea300 of the eye is diagrammatically illustrated. FIG. 24A illustrates across-sectional view of the eye, whereas FIG. 24B illustrates a frontview of the eye. The formation of the intracorneal pocket 302 in thecornea 300 of the eye allows one to gain access to the tissue boundingthe pocket 302 (i.e., the interior stromal tissue bounding the pocket302). In particular, as shown in the illustrative embodiment of FIG.24A, the pocket 302 is formed by making an intrastromal incision in thecornea 300 of the eye using either a femtosecond laser (i.e., theincision is cut in the cornea 300 using the laser beam(s) emitted fromthe femtosecond laser) or a mechanical keratome (e.g., a mechanicalmicrokeratome).

After the pocket 302 is cut using the femtosecond laser or mechanicalkeratome, a photosensitizer is applied inside the pocket so that thephotosensitizer permeates the tissue bounding the pocket 302. Thephotosensitizer facilitates the cross-linking of the tissue bounding thepocket 302. In the illustrative embodiment, the photosensitizer isinjected with a needle inside the stromal pocket without lifting theanterior corneal stroma so as to cover the internal surface of thecorneal pocket 302 (e.g., as shown in FIG. 10). In one or moreembodiments, the photosensitizer or cross-linker that is injectedthrough the needle inside the stromal pocket comprises riboflavin,and/or a liquid suspension having nanoparticles of riboflavin disposedtherein. Preferably, the cross-linker has between about 0.1% riboflavinto about 100% riboflavin therein (or between 0.1% and 100% riboflavintherein). Also, in one or more embodiments, an excess portion of thephotosensitizer in the pocket 302 may be aspirated through the needleuntil all, or substantially all, of the excess portion of thephotosensitizer is removed from the pocket 302 (i.e., the excesscross-linker may be aspirated through the same needle so that the pocket302 may be completely emptied or substantially emptied).

Next, turning to the illustrative embodiment of FIG. 25A, shortly afterthe photosensitizer is applied inside the pocket, the cornea 300 of theeye is irradiated from the outside using ultraviolet (UV) radiation 304so as to activate cross-linkers in the portion of the tissue boundingthe pocket 302, and thereby stiffen the cornea 300, prevent cornealectasia of the cornea 300, and kill cells in the portion of the tissuebounding the pocket 302. In the illustrative embodiment, the ultravioletlight used to irradiate the cornea 300 may have a wavelength betweenabout 370 nanometers and about 380 nanometers (or between 370 nanometersand 380 nanometers). Also, in the illustrative embodiment, only apredetermined anterior stromal portion 306 of the cornea 300 to whichthe photosensitizer was applied is cross-linked (i.e., the bounding wallof the corneal pocket 302), thereby leaving an anterior portion of thecornea 300 and a posterior stromal portion of the cornea 300uncross-linked. That is, in the illustrative embodiment, the entirecorneal area inside the cornea 300 exposed to the cross-linker isselectively cross-linked, thereby leaving the anterior part of thecornea 300 and the posterior part of the stroma uncross-linked. Theportion of the cornea 300 without the cross-linker is not cross-linkedwhen exposed to the UV radiation. In an alternative embodiment, thecornea 300 may be irradiated using microwaves as an alternative to, orin addition to being irradiated using the ultraviolet (UV) radiation 304depicted in FIG. 25A.

Now, with reference to FIGS. 26A and 26B, it can be seen that, after thecornea 300 has been stiffened and is devoid of cellular elements by theactivation of the cross-linkers, a lens implant 308 is inserted into thecorneal pocket 302 in order to change the refractive properties of theeye. FIG. 26A illustrates a cross-sectional view of the eye depictingthe implantation of the intracorneal lens implant 308, whereas FIG. 26Billustrates a front view of the eye depicting the implantation of theintracorneal lens implant 308. In particular, in the illustratedembodiment, the lens implant 308 is inserted through a small incision,and into the corneal pocket 302, using forceps or microforceps 310. Inone or more embodiments, the lens implant 308 that is inserted insidethe pocket 302 in the cornea 300 is flexible and porous. Also, in one ormore embodiments, the lens implant 308 may comprise a hybrid lensimplant with an organic outer portion and a synthetic inner portion. Theorganic outer portion of the hybrid lens implant may be made from atransparent, hydrophilic organic polymer, while the synthetic innerportion of the hybrid lens implant may be made from a transparent, gaspermeable, porous flexible polymer. For example, the transparent,hydrophilic polymer forming the organic outer portion may be formed fromcollagen, chitosan, poloxamer, polyethylene glycol, or a combinationthereof (or any other transparent hydrophilic coating which can bedeposited over the entire lens surface), while the flexible polymerforming the synthetic inner portion of the hybrid lens implant may beformed from silicone, acrylic, polymetacrylate, hydrogel, or acombination thereof. The surface of the lens implant 308 may have theappropriate shape to reshape the cornea 300 or the dioptric power tonullify the remaining spheric or astigmatic error of the eye. Moreparticularly, in one or more embodiments, the lens implant 308 may haveone of: (i) a concave surface to correct myopic refractive errors (i.e.,a minus lens for correcting nearsightedness), (ii) a convex surface tocorrect hyperopic refractive errors (i.e., a plus lens for correctingfarsightedness), or (iii) a toric shape to correct astigmatic refractiveerrors. In one or more embodiment, the lens implant 308 may have anysuitable shape (e.g., circular, annular, etc.) for correcting aparticular error of the eye, and may be implanted in any suitablelocation within the cornea 300 for correcting the particular error ofthe eye.

In the illustrative embodiment, the irradiation of the cornea 300 usingthe ultraviolet (UV) radiation 304 only activates cross-linkers in theportion of the stromal tissue bounding the pocket 302, and only killsthe cells in the portion of the tissue bounding the pocket 302, so as toleave only a thin layer (e.g., between 20 and 30 microns) ofcross-linked collagen to prevent rejection of the lens implant 308and/or encapsulation by fibrocytes, while preventing post-operative dryeye formation. In addition to preventing encapsulation of the lensimplant 308 by fibrocytes, the cross-linking of the stromal tissuebounding the pocket 302 also advantageously prevents corneal hazeformation around the lens implant 308. That is, the cross-linking of thestromal tissue surrounding the lens implant 308 prevents formation ofmyofibroblast from surrounding keratocytes, which then convert graduallyto fibrocytes that appear as a haze, and then white encapsulation insidethe cornea, thereby causing light scattering in front of the patient'seye.

In one or more further embodiments, after the lens implant 308 has beeninserted into the pocket 302, an additional amount of photosensitizer(e.g., an additional amount of riboflavin) is injected into the pocket302, and the cornea 300 is irradiated an additional time so as tofurther stiffen stromal tissue of the cornea and expand the area ofacellular collagenous stromal tissue surrounding the lens implant 308 toprevent rejection of the lens implant 308 and/or encapsulation of thelens implant 308 by fibrocytes, while preventing post-operative dry eyeformation. That is, the area of acellular collagenous stromal tissuesurrounding the lens implant 308 is able to be cross-linked repeatedlythrough the use of additional riboflavin injections so that the area ofintrastromal crosslinking may be extended, and to prevent implantrejection and cellular fibrosis formation at any time after the initialprocedure. This additional cross-linking still leaves the anteriorstromal nerves intact and uncross-linked so as to not produce dry eyeformation.

Referring again to the illustrative embodiment of FIGS. 24A-27B, afterthe lens implant 308 has been inserted into the pocket 302 in the cornea300 of the eye, laser energy is applied to the lens implant 308 in thepocket 302 using a laser 312 so as to correct refractive errors of thelens implant 308 and/or the eye in a non-invasive manner (refer to FIG.27A). In the illustrative embodiment, a two-photon or multi-photon laser312 is used to apply the laser energy to the lens implant 308 in thepocket 302 so as to modify the index of refraction of a discreteinternal part of the lens implant 308 in a non-invasive manner, whilepreventing post-operative dry eye formation. In the illustrativeembodiment, the laser energy applied by the two-photon or multi-photonlaser has a predetermined energy level below an optical breakdown powerlevel of the two-photon or multi-photon laser. The fast-acting, shortlaser pulse of the two-photon or multi-photon laser 312 is used tomodify the refractive power of the lens implant 308. In the illustrativeembodiment, the two-photon or multi-photon laser 312 is not used tomodify the shape of the lens implant. In the illustrative embodiment,the multi-photon laser may comprise a three-photon laser, etc. Also, inthe illustrative embodiment, the two-photon or multi-photon laser is aspecific type of femtosecond laser.

In the illustrative embodiment, the laser beam(s) emitted by thetwo-photon or multi-photon laser 312 heats up the lens implant 308, andthereby modifies the index of refraction of the lens implant 308 (i.e.,it creates a more positive or negative lens). Because a two-photon ormulti-photon laser 312 comprises two or more laser beams that cometogether at the focal point of the laser, less energy is passing throughthe anterior corneal tissue disposed in front of the lens implant 308.Thus, advantageously, in the illustrative embodiment, the two-photon ormulti-photon laser 312 does not damage the surface of the cornea or thecorneal tissue anteriorly disposed relative to the lens implant 308. Inthe illustrative embodiment, the two-photon or multi-photon laser 312modifies the interior of the lens implant 308 (i.e., by modifying itsrefractive index), but it does not modify the surface of the lensimplant 308 or the corneal tissue disposed anteriorly disposed relativeto the lens implant 308. In the illustrative embodiment, the laserbeam(s) of the two-photon or multi-photon laser 312 may have awavelength between about 700 nanometers and about 1100 nanometers (orbetween 700 nanometers and 1100 nanometers). In the illustrativeembodiment, the two-photon or multi-photon laser 312 does not require aphotosensitizer, and the laser beams emitted thereby may penetratebetween 100 and 400 microns into the interior of the cornea.

In one or more embodiments, prior to the application of the laser energyto the lens implant 308 in the pocket 302 by the two-photon ormulti-photon laser 312, a virtual model of the lens implant 308 isgenerated, and the two-photon or multi-photon laser 312 is focused inaccordance with the virtual model. In particular, a specially programmeddata processing device (i.e., a specially programmed computing device orcomputer) is used to generate a virtual model of the lens implant 308 sothat a new index of refraction of the lens implant 308 at the focalpoint of the two-photon or multi-photon laser 312 is capable of beingdetermined prior to the application of the two-photon or multi-photonlaser 312. Then, the specially programmed data processing device (i.e.,a specially programmed computing device or computer) is used to focusthe two-photon or multi-photon laser 312 non-invasively outside the eyein accordance with the virtual model generated for the lens implant 308.

In one or more further embodiments, a femtosecond laser, a two-photonlaser, or a multi-photon laser may be used to apply laser energy to thelens implant 308 in the pocket 302 in order to increase the index ofrefraction of a particular area of the lens implant (e.g., by creating aprismatic line on the surface of the lens or inside of the lens), andthereby convert the lens implant from a monofocal lens to a bifocal lensor trifocal lens. In these further embodiments, the particular area ofthe lens implant 308 that the index of refraction is increased maycomprise one of: (i) an area slightly below the cornea or the centralvisual axis of the eye, (ii) a central area centrally located on thecentral visual axis of the eye, and (iii) a peripheral areacircumscribing the central visual axis of the eye. For example, in oneembodiment, the particular area of the lens implant 308 that is modifiedmay be 2-3 mm in diameter to correct presbyopia in an older person. Theindex of refraction of the particular area of the lens implant 308 maybe modified to correct myopic refractive errors (i.e., nearsightedness),hyperopic refractive errors (i.e., farsightedness), or astigmaticrefractive errors. Because the lens implant 308 can be removed from theeye (e.g., using a spatula), and replaced, the entire refractive errorcorrection process described above can be reversible, and is capable ofbeing repeated.

Also, in one or more further embodiments, a femtosecond laser, atwo-photon laser, or a multi-photon laser may be used to apply laserenergy to the lens implant 308 in the pocket 302 in order to creatediffractive portions within the lens implant 308, thereby resulting in abifocal lens comprising both refractive and diffractive lens portions.

In the method described above, as illustrated in FIGS. 24A-27B, aphotorefractive keratectomy (PRK) procedure is not performed on thefront surface of the cornea 300 so that the front surface of the cornea300 is not required to be ablated by an excimer laser. Also, alaser-assisted in situ keratomileusis (LASIK) procedure is not performedon the cornea 300 of FIGS. 24A-27B so that a flap is not required to beformed in the cornea 300, thereby preventing a formation of dry eye in apatient resulting from the severing of the corneal nerves supplying thefront surface of the cornea 300. That is, with the method describedabove, it is not necessary to form a LASIK flap, which requires severingthe corneal nerves about a 300 degree area of the cornea. In somepatients, it can take over a year to recover from the dry eye thatresults from the formation of the flap during the LASIK procedure.

In a second illustrative embodiment of the intracorneal lensimplantation procedure with the cross-linking of the cornea, a lensimplant is soaked in a crosslinking solution prior to be inserted intothe eye of the patient. As will be described in further detailhereinafter, this method generally includes soaking a lens implant in acrosslinking solution, forming a pocket in the cornea of an eye,inserting the lens implant in the pocket, cross-linking the interiorstroma of the cornea, and then applying laser energy to the lens implantin the pocket using a laser to correct refractive errors of the lensimplant and/or the eye in a non-invasive manner. As in the firstillustrative embodiment of the intracorneal lens implantation procedureexplained above, no flap is formed in the cornea of the eye. Also, thefront surface of the cornea is not ablated using a PRK procedure.

Initially, in the second illustrative embodiment of the intracorneallens implantation procedure, a lens implant is soaked in a cross-linkingsolution held in a container prior to its insertion into a cornealpocket in the eye so that the lens implant is pre-coated with thecross-linking solution thereon. The lens implant has a predeterminedshape for changing the refractive properties of an eye, and is flexibleand porous so that fluids (e.g., oxygen, electrolytes, glucose, etc.)are able to freely pass through the lens implant. In the secondillustrative embodiment, the lens implant may comprise a hybrid lensimplant as described above with regard to the first illustrativeembodiment, or may comprise any of the other characteristics describedabove with regard to the lens implant 308. The coated surface of thehybrid lens implant may be organic and hydrophilic, and may formed usinga desired thickness that can be cross-linked with UV light andriboflavin before or after its implantation. Also, in the secondillustrative embodiment, the cross-linking solution may comprise aphotosensitizer in the form of riboflavin, and/or a liquid suspensionhaving nanoparticles of riboflavin disposed therein. Preferably, thecross-linker has between about 0.1% riboflavin to about 100% riboflavintherein (or between 0.1% and 100% riboflavin therein).

Next, in the second illustrative embodiment of the intracorneal lensimplantation procedure, a pocket is formed in the cornea of the eye. Theformation of the corneal pocket in the cornea of the eye allows one togain access to the tissue bounding the pocket (i.e., the interiorstromal tissue bounding the pocket). In particular, in the secondillustrative embodiment, the pocket is formed by making an intrastromalincision in the cornea of the eye either by using a femtosecond laser(i.e., the incision is cut in the cornea using the laser beam(s) emittedfrom the femtosecond laser) or by using a mechanical keratome (e.g., amechanical microkeratome).

After the pocket is formed in the cornea of the eye, the lens implantwith the photosensitizer provided thereon (e.g., riboflavin) is insertedinside the pocket so that the photosensitizer permeates at least aportion of the tissue bounding the pocket. In particular, in theillustrated embodiment, the lens implant is inserted into the cornealpocket through a very small incision using a pair of forceps ormicroforceps. The photosensitizer facilitates the cross-linking of theportion of the tissue bounding the pocket.

Then, shortly after the lens implant with the photosensitizer isinserted inside the pocket, the cornea of the eye is irradiated from theoutside using ultraviolet (UV) radiation so as to activate cross-linkersin the portion of the tissue bounding the pocket, and thereby stiffenthe cornea, prevent corneal ectasia of the cornea, and kill cells in theportion of the tissue bounding the pocket. In the illustrativeembodiment, the ultraviolet light used to irradiate the cornea may havea wavelength between about 370 nanometers and about 380 nanometers (orbetween 370 nanometers and 380 nanometers). Also, in the illustrativeembodiment, only a predetermined anterior stromal portion of the corneato which the photosensitizer was applied from the lens implant iscross-linked (e.g., only the bounding wall of the corneal pocket),thereby leaving an anterior portion of the cornea and a posteriorstromal portion of the cornea uncross-linked. That is, in theillustrative embodiment, the entire corneal area inside the corneaexposed to the cross-linker is selectively cross-linked, thereby leavingthe anterior part of the cornea and the posterior part of the stromauncross-linked. The portion of the cornea without the cross-linker isnot cross-linked when exposed to the UV radiation. In an alternativeembodiment, the cornea may be irradiated using microwaves as analternative to, or in addition to being irradiated using ultraviolet(UV) radiation.

In the second illustrative embodiment of the intracorneal lensimplantation procedure, the irradiation of the cornea using theultraviolet (UV) radiation only activates cross-linkers in the portionof the stromal tissue bounding the pocket, and only kills the cells inthe portion of the tissue bounding the pocket, so as to leave only athin layer of cross-linked collagen to prevent rejection of the lensimplant and/or encapsulation by fibrocytes, while preventingpost-operative dry eye formation. In addition to preventingencapsulation of the lens implant by fibrocytes, the cross-linking ofthe stromal tissue bounding the pocket also advantageously preventscorneal haze formation around the lens implant. That is, thecross-linking of the stromal tissue surrounding the lens implantprevents formation of myofibroblast from surrounding keratocytes, whichthen convert gradually to fibrocytes that appear as a haze, and thenwhite encapsulation inside the cornea, thereby causing light scatteringin front of the patient's eye.

After the lens implant has been inserted into the pocket in the corneaof the eye, laser energy is applied to the lens implant in the pocketusing a laser so as to correct refractive errors of the lens implantand/or the eye in a non-invasive manner. In the second illustrativeembodiment, a two-photon or multi-photon laser is used to apply thelaser energy to the lens implant in the pocket so as to modify the indexof refraction of a discrete internal part of the lens implant in anon-invasive manner, while preventing post-operative dry eye formation.In the second illustrative embodiment, the laser energy applied by thetwo-photon or multi-photon laser has a predetermined energy level belowan optical breakdown power level of the two-photon or multi-photonlaser.

As described above with regard to the first illustrative embodiment ofthe intracorneal lens implantation procedure, prior to the applicationof the laser energy to the lens implant in the pocket by the two-photonor multi-photon laser, a virtual model of the lens implant may begenerated, and the two-photon or multi-photon laser may be focused inaccordance with the virtual model. In particular, a specially programmeddata processing device (i.e., a specially programmed computing device orcomputer) is used to generate a virtual model of the lens implant sothat a new index of refraction of the lens implant at the focal point ofthe two-photon or multi-photon laser is capable of being determinedprior to the application of the two-photon or multi-photon laser. Then,the specially programmed data processing device (i.e., a speciallyprogrammed computing device or computer) is used to focus the two-photonor multi-photon laser non-invasively outside the eye in accordance withthe virtual model generated for the lens implant.

In a third illustrative embodiment of the intracorneal lens implantationprocedure with the cross-linking of the cornea, the procedure may beperformed in a similar manner to that described above with regard to thesecond illustrative embodiment, except that the laser energy may beapplied to the lens implant in the pocket by the laser prior to theirradiation of the cornea, rather than after the irradiation of thecornea as described above in the second embodiment.

Any of the features, attributes, or steps of the above describedembodiments and variations can be used in combination with any of theother features, attributes, and steps of the above described embodimentsand variations as desired.

Although the invention has been shown and described with respect to acertain embodiment or embodiments, it is apparent that this inventioncan be embodied in many different forms and that many othermodifications and variations are possible without departing from thespirit and scope of this invention.

Moreover, while exemplary embodiments have been described herein, one ofordinary skill in the art will readily appreciate that the exemplaryembodiments set forth above are merely illustrative in nature and shouldnot be construed as to limit the claims in any manner. Rather, the scopeof the invention is defined only by the appended claims and theirequivalents, and not, by the preceding description.

The invention claimed is:
 1. A method of intracorneal lens implantationwith a cross-linked cornea, said method comprising: soaking a lensimplant in a cross-linking solution that includes a photosensitizer, thelens implant having a predetermined shape for changing the refractiveproperties of an eye; forming a pocket in a cornea of the eye; after thepocket in the cornea has been formed, inserting the lens implant withthe photosensitizer thereon inside the pocket so that thephotosensitizer permeates at least a portion of the tissue bounding thepocket, the photosensitizer facilitating cross-linking of the portion ofthe tissue bounding the pocket; irradiating the cornea so as to activatecross-linkers in the portion of the tissue bounding the pocket, andthereby stiffen the cornea, prevent corneal ectasia of the cornea, andkill cells in the portion of the tissue bounding the pocket; andapplying laser energy to the lens implant in the pocket using atwo-photon or multi-photon laser so as to modify the index of refractionof a discrete internal part of the lens implant to correct the remainingrefractive errors of the eye in a non-invasive manner, while preventingpost-operative dry eye formation; wherein the step of irradiating thecornea so as to activate cross-linkers in the portion of the tissuebounding the pocket only kills the cells in the portion of the tissuebounding the pocket so as to leave only a thin layer of cross-linkedcollagen to prevent rejection of the lens implant and/or encapsulationby fibrocytes, while preventing post-operative dry eye formation.
 2. Themethod according to claim 1, wherein the photosensitizer of thecross-linking solution comprises riboflavin.
 3. The method according toclaim 1, wherein the step of irradiating the cornea so as to activatecross-linkers in the portion of the tissue bounding the pocket comprisesirradiating the cornea with ultraviolet light.
 4. The method accordingto claim 1, wherein the step of inserting the lens implant with thephotosensitizer thereon inside the pocket comprises inserting the lensimplant using forceps.
 5. The method according to claim 1, wherein thelens implant that is inserted inside the pocket in the cornea isflexible and porous.
 6. The method according to claim 1, wherein thelens implant comprises a hybrid lens implant with an organic outerportion and a synthetic inner portion, the organic outer portion of thehybrid lens implant being made from a transparent, hydrophilic organicpolymer, and the synthetic inner portion of the hybrid lens implantbeing made from a transparent, gas permeable, porous flexible polymer.7. The method according to claim 1, wherein the lens implant has one of:(i) a concave surface to correct myopic refractive errors, (ii) a convexsurface to correct hyperopic refractive errors, or (iii) a toric shapeto correct astigmatic refractive errors.
 8. The method according toclaim 1, wherein, prior to the step of applying laser energy to the lensimplant in the pocket, performing the additional steps of: generating,by using a specially programmed data processing device, a virtual modelof the lens implant so that a new index of refraction of the lensimplant at the focal point of the two-photon or multi-photon laser iscapable of being determined prior to the application of the two-photonor multi-photon laser; and focusing, by using the specially programmeddata processing device, the two-photon or multi-photon lasernon-invasively outside the eye in accordance with the virtual modelgenerated for the lens implant.
 9. A method of intracorneal lensimplantation with a cross-linked cornea, said method comprising: soakinga lens implant in a cross-linking solution that includes aphotosensitizer, the lens implant having a predetermined shape forchanging the refractive properties of an eye; forming a pocket in acornea of the eye; after the pocket in the cornea has been formed,inserting the lens implant with the photosensitizer thereon inside thepocket so that the photosensitizer permeates at least a portion of thetissue bounding the pocket, the photosensitizer facilitatingcross-linking of the portion of the tissue bounding the pocket; applyinglaser energy to the lens implant in the pocket using a two-photon ormulti-photon laser so as to modify the index of refraction of a discreteinternal part of the lens implant to correct the remaining refractiveerrors of the eye in a non-invasive manner, while preventingpost-operative dry eye formation; and after the laser energy has beenapplied to the lens implant, irradiating the cornea so as to activatecross-linkers in the portion of the tissue bounding the pocket, andthereby stiffen the cornea, prevent corneal ectasia of the cornea, andkill cells in the portion of the tissue bounding the pocket; wherein thestep of irradiating the cornea so as to activate cross-linkers in theportion of the tissue bounding the pocket only kills the cells in theportion of the tissue bounding the pocket so as to leave only a thinlayer of cross-linked collagen to prevent rejection of the lens implantand/or encapsulation by fibrocytes, while preventing post-operative dryeye formation.